Several pregnancy termination methods are available in medical or surgical abortion: 1) an `ordinary abortion` with preoperative ripening of the cervix followed by a vacuum aspiration under heavy sedation; 2) a modified Karman exeresis with a paracervical block; 3) a medical abortion with RU486 and prostaglandin.
Medical termination of pregnancy (medical abortion) as an alternative to surgical abortion has many advantages since it does not require anesthetics and there is no risk of cervical laceration or uterine perforation (Harvey et al. 1995). RU486 (mifepristone) is a best example as an abortifacient medical agent for non-surgical abortion (Cadepond et al. 1997). It is the first steroidal antiprogesterone in clinical use (Cameron et al. 1986; Bygdeman and Van Look 1988). It acts by binding to progesterone receptor, thus blocking the effects of progesterone at the uterine level, and provoking endometrial necrosis and shedding. RU486 can, therefore, be used to interrupt early human pregnancy. In pregnancy of up to 7-8 weeks duration, the rate of completed abortions with RU486 alone has ranged from 50% to 90%. The success rate can, however, be increased up to 95.about.100% by combining RU486 with a low dose prostaglandin. In addition, possible clinical uses of RU486 include induction of menstruation, late post-coital contraction, induction of labor after intrauterine fetal death, preoperative cervical ripening and treatment of progesterone receptor positive mammary tumors.
Although research has focused on an isolation of abortifacient medical agents that can effectively and safely terminate pregnancy, most of abortifacient medical agents alone do not result in complete abortion. Therefore, a combination of medical agents is commonly used to induce complete abortion (Cameron et al. 1986; el-Refaey and Templeton 1995). An approach to screening large numbers of substances to identify potential abortifacient agents would allow identification of more effective, safe and rapid medical abortion agents that can be used alone or in combination with other agents.
Placenta provides maintenance, nourishment, and protection of the fetus during development and is vital to the survival of the fetus (Cross et al. 1994). Although embryos with organ defects can survive to term, defects in placentation usually results in embryonic death, which reflects the importance of the placenta during embryogenesis. Even seemingly minor defects in placentation can have severe negative consequences. In human, for example, abnormalities in the vascular connections result in preeclampsia, a disease of pregnancy with significant morbidity and mortality to both mother and fetus (Roberts et al. 1993). Such disorders not only affect the health of the mother and fetus, but also represent significant societal costs. Currently, the approaches for the diagnosis and treatment of diseases of pregnancy are limited because of the small number of molecular markers truly specific to the trophoblast cells and our inability to understand their causes.
During mammalian development, the trophoblast is the first lineages to differentiate and gives rise to most of the extraembryonic tissues which are required for implantation and further development of the embryo proper within the uterine environment (Rossant 1986; Cross et al. 1994). It arises from the trophectoderm of the blastocyst and contributes predominantly to the fetal portion of the mature placenta in later development. Human trophoblast in normal implantation and placentation appears to undergo two different pathways of differentiation resulting in the development of villous and extravillous trophoblast (Kurman et al. 1984; Loke and King 1995). Cytotrophoblast (CT) differentiates abruptly into syncytiotrophoblast (ST) on the villous surface as compared with the spectrum of differentiation exhibited by extravillous trophoblast where CT differentiates into intermediate trophoblast (IT) and then into multinucleated intermediate trophoblastic cells (MITC). The various types of gestational trophoblast lesions can be defined and related to discrete pathologic aberrations occurring at different stages of trophoblastic differentiation (Lim et al. 1997; Horn and Bilek 1997; Shin and Kurman 1997).
Therefore, the discovery of trophoblast-specific markers can facilitate the molecular dissection of the lineage and differentiation stages of trophoblast and relate these to various trophoblastic lesions (Mazur and Murman 1994). Furthermore, antibodies against these markers will have considerable value in the study and differential diagnosis of different types of gestational trophoblastic diseases (Losch and Kainz 1996).
The mature murine placenta is composed of three trophoblast layers, namely, the labyrinthine trophoblast, spongiotrophoblast, and giant cell layers, which are each morphologically distinct (Rossant and Croy 1985; Rossant 1995). These specialized murine trophoblast cell types, labyrinthine trophoblast, spongiotrophoblast, and giant cells are homologous to the syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast in human placenta, respectively.
We have recently described a novel homeobox-containing gene, Psx, which was isolated from mouse conceptus (Han et al. 1998). It is well known that homeobox genes are involved in controlling cell fates such as body plan during embryo development (De Robertis 1994). Therefore, single mutation can induce major change of the body plan and altered expression of homeobox genes were detected in tumor or malignant transformation. The homeobox genes are characterized by a conserved 180-bp nucleotide sequence known as the homeobox, which encodes a 60-amino acid DNA binding homeodomain structured in three .alpha.-helices (Gehring et al. 1994). This DNA binding property indicates that homeodomain proteins function as transcription factors in controlling downstream target genes. In animals, most of these genes have been shown to regulate the coordinated expression of multiple genes involved in development, differentiation and malignant transformation (McGinnis and Krumlauf 1992).
The expression of this gene is first detected at embryonic day 8.5 and limited to the placenta, especially to the trophoblast cell layers of placenta. Therefore, these findings suggest that Psx plays a significant role in the development of placentation, especially in the development of trophoblast specific cell lineages. Accordingly, Psx gene and gene product would be useful as a new trophoblast-specific and stage-specific marker and also in developing therapeutic strategies for the treatment of disorders involving the trophoblast-specific Psx-mediated diseases such as gestational trophoblastic diseases.